Schizophrenia is a mental illness that results in tremendous human suffering and monetary costs to society. Understanding the neuropathologies mediating schizophrenia through the use of animal models will lead to better treatments. One realistic approach to model development is to model specific psychological constructs that are affected by the disorder of interest. Accordingly, this application focuses on continuing the development and validation of two distinct rat models of a cluster of schizophrenia symptoms called negative symptoms. It is hypothesized that the negative symptoms reflect deficits in reward and motivational processes that are operationally defined as elevations in brain reward thresholds induced by manipulations (phencylidine withdrawal and amphetamine withdrawal) that induce behavioral and neurobiological abnormalities relevant to the negative symptoms of schizophrenia. These drug withdrawal models of the negative symptoms should not be confused with models acute effects of these drugs hypothesized to reflect the positive symptoms of schizophrenia. SPEC. AIMS: Specific Aims 1 and 2 will continue to explore whether decreases in brain reward function associated with either phencyclinde or amphetamine withdrawal are valid models of the negative symptoms by testing whether these reward deficits are reversed by atypical, but not typical, antipsychotics. This prediction is based on clinical data that typical antipsychotics are ineffective against negative symptoms, while atypical show some therapeutic efficacy against these symptoms. Preliminary data support the above predictions. Specific Aims 3 & 4 will investigate the neurobiology of these reward deficits, and the neurobiology of the reversal of these deficits by pharmacological treatments. Aim 3 will test whether selective antagonists for the 5-HT2 and alpha2 adrenergic receptors will reverse the reward deficits in the models. These antagonists were selected based on a theoretical rationale indicating a role of the neurotransmitter systems probed by these antagonists in the negative symptoms, and the receptor profile of atypical antipsychotics. Aim 4 will use the models developed and the oligonucleotide microarray technology to explore gene expression changes associated with reward deficits, and gene expression changes associated with the reversal of the reward deficits. Follow-up studies will validate the results provided by microarrays. These studies will provide rat models of the negative symptoms that have been dificult to model, and will explore the neurobiology of these symptoms using behavioral, pharmacological and molecular biological techniques. Such studies will lead to better treatments for schizophrenia.